Antifungals

Question 1

Classification of Mycoses

Answer 1

System (potentialy life threatening)

Superficial

Question 2

Antifungal Targets

Answer 2

Targets:
membranes (ergosterol)
nucleic acids
cell wall

Question 3

Drugs for systemic fungal infections

Answer 3

Amphotericin B
Flucytoisne
Imidazoles (fluconazole, itraconazole, voriconazole)
Capsofungin

Question 4

Amphotericin B

Answer 4

Effective for most serious systemic mycoses especially those are life threatening immediately
Gold standard for anti-fungal effectiveness by which other drugs are judged
Side effects: so use for proven of highly suspected systemic infections (Total cumulative dose is important for reasons permanent renal toxicity)
fever, nausea, vomiting, headache, chills, hypotension, hypokalemia, tachypnea, 90% with nonpermanent nephrotoxicity (permanent renal damage occurs depending of total dose), reversible hypochromic, normocytic anemia
Only fungistatic at serum levels in human

Question 5

MOA Amphotericin B

Answer 5

Binds to ergosterol in membrane causes membrane leakiness (causes holes)

Question 6

Flucytosine (5-FC)

Answer 6

Serious infections: Candida, Cryptococcus
Used in conjunction (synergistic) with amphotericin B
Side effects: nausea, vomiting, diarrhea, enterocolitis, Leukopnia thrombocytopenia, extreme caution with renal insufficiency or bone marrow depression, reversible elevated hepatic enzymes

Question 7

Fluctyosine (5-FC)

Answer 7

fungal cytosine deaminase which converts cytosine permease to 5 FU
which inhibits DNA synthesis

Question 8

Triazoles

Answer 8

fluconazole
voriconazole
itraconazole

Question 9

Triazole MoA and Side effects

Answer 9

Inhibit 14 alpha sterol demethylase, fungal cytochrome P450 that converts lanosterol to erosterol
Net effect is inhibition of ergosterol synthesis
This is slower onset mechanism
Side effects: nausea, vomiting, rash, diarrhea, headache, mild hepatotoxicity (discontinue with onset of liver dysfunction)
Inhibits metabolism of several other drugs (CYP3A and 2C families) because inhibit CYP450s

Question 10

Fluconazole

Answer 10

Cryptococcus
Candida (many sites including CNS and urinary)
most C. albicans, some C. glabrata, not C. krusei (narrow spectrum of Candida)
CNS penetration: yes
Active drug in urine
Lowest incidence of hepatotoxicity among the azole antifungals

Question 11

Itraconazole

Answer 11

Blastomyces
Histoplasma
Candia (esophagus and oropharynx but not CNS and urinary)
More albicans and glabrata and some C. krusei
No CNS penetration or active drug in urine
Contraindications: do not give with other drugs that are metabolized by CYP3A4
can cause potential for severe CV events including death

Question 12

Voriconazole

Answer 12

Aspergillus
Candida (not urinary)
covers many species including glabrata and krusei
Limited CNS penetration and no active drug in urine
Side effects: visual distrubances (30%), phosensitive component to rash

Question 13

Anti-fungals that Target Cell Wall

Answer 13

caspofungin

Question 14

Caspofungin

Answer 14

Treat invasive Aspergillus (intolerant to other drugs), Candida (esophageal and systemic and broad coverage of glabra and krusei)
MOA: inhibit fungal cell wall synthesis by noncompeitively blocking synthesis of B(1,3)-D-glucan in filamentous fungi
No cross resistance with imidazoles and triazoles
Side effects: fever, nausea, flushing, phlebitis at injection site

Question 15

Treatment of Superficial Mycoses

Answer 15

Nystatin
Imidazoles (fluconazole, miconazole, clotrimazole, itraconazole)
Opthalmic : natamycin

Question 16

Fluconazole

Answer 16

Candida infections (vaginal, urinary track, oropharynx)
Oral not topical

Question 17

Miconazole

Answer 17

Topical: creams/suppositories for vaginal Candida

Question 18

Clotrimazole

Answer 18

Candia
topical use (oral troches or vaginal creams/solutions)
Side effect or oral troches: abnormal liver function test

Question 19

Itraconazole

Answer 19

Candida: oropharyngeal and esophageal (oral not topical)

Question 20

Nystatin

Answer 20

Mechanism similar to amphotericin B (effecitve against -azole-resistant strains)
Topical use for Candida (skin, mucous membrane, vaginal)
Oral use for GI tract Candida (not absorbed systemically)
Side effects: oral has GI distress and bad taste

Question 21

Amphotericin B

Answer 21

Topical

Cutaneous or mucosal Candida (not for dermatophytes

Question 22

Treatment of Opthalmic fungal infections

Answer 22

Natamycin- opthalmic infections
Mechanism similar to amphotericin B
not systemically because too toxic
toxicity: conjunctival chemosis and hyperemia

Question 23

Topical Treatment for Dermatophytes (Tinea pedis, Tinea cruris, Tinea corporis)

Answer 23

Miconazole, clotrimazole
Tolnaftate
Terbinafine
Ciclopirox (nail laquer)

Question 24

Topical Treatment for Fungal Nail Infections

Answer 24

Ciclopirox- FDA approved topical for mld to moderate fungal nail infections
mechanism: inhibit metal dependent fungal enzymes by metal chelation

Question 25

Terbinafine

Answer 25

Oral drugs 12 week therapy for nail infections deposit and stay in tissue for a long time also shorter duration of therapy for tinea capitis MOA: blocks early in pathway from blocking squalene to 2,3-oxidosqualene upstream of ergosterol and fungicidal because squalene accumulates and disrupt fungal cell membrane Side effects: diarrhea, dyspepsia, abdominal pain

Question 26

Griseofulvin

Answer 26

for recalcitrant dermatophytic infections of skin, hair, nails Therapy for tinea capitis Mechanism: interfere with microtubule function/mitotic spindle/mitosis Side effects: contraindicated in those with prophyria and advanced liver disease, inreased metabolism of several drugs (CYP inducer), Use with caution with those with penicillin allergies

Question 27

Itraconazole

Answer 27

Oral therapy for fungal toenail infections Side effects: nausea, vomiting, rash, diarrhea, headache, edema, inhibits metabolism of many drugs, discontinue if signs of liver dysfunction

Question 28

Oral Antifungal dermatophytes

Answer 28

Itraconazole Griseofulvin Terbinafine